1. Field of the Invention
The present invention relates to novel benzopyran derivatives substituted with secondary amines including imidazole of formula 1. It also relates to process for preparing the novel compounds and pharmaceutical formulations comprising one or more of the compounds as an active ingredient.
The present invention also relates to pharmaceutical use of the benzopyran derivatives substituted with secondary amines including imidazole. In particular, the present invention is pharmacologically useful in the treatment of cancer, rheumatoid arthritis, and diabetic retinopathies through anti-angiogenic properties, and also pharmacologically useful for the protection of heart, neuronal cells, brain injury, organs for preservation or in major cardiovascular surgery against ischemia-reperfusion injury or oxidative stress.

Wherein R1, R2, R3, R4 and * are each defined in specification.
2. Description of the Prior Art
The ratio of cancer in human diseases is being gradually increased despite the considerable research has been devoted to the whole area of cancer. Since the 1970s discovery by J. Folkman that angiogenesis, the formation of new blood vessels from preexisting vessels, is implicated in tumor growth, anti-angiogenics have been identified as one of the most promising and innovative drug classes.
Traditional chemotherapeutics destroy tumor cell populations by chemical poisoning of cancer cells during their productive cycles, which affect normal cells as well as tumor cells resulting in serious side effects. Therefore, the research on the development of anti-angiogenic agents, which inhibit the formation of new blood vessels to provide oxygen and nutrients, and to provide a way to metastasize to distant organs, is considered as one of the novel approaches for the anti-cancer therapies.
While angiogenesis normally occurs in adults only in the specific conditions such as wound healing and inflammation, angiogenesis is recognized as the core process for growth and metastasis of solid tumors because solid tumors could only grow to 1-2 mm without developing a blood supply (Folkman, J. et al., J. Biol. Chem. 267: 10931-10934 (1992)). In normal conditions the angiogenic process is under tight regulation of stimulatory and inhibitory factors. Under certain pathological conditions such as the growth of solid tumors, rheumatoid arthritis, psoriasis, complications of AIDS, and diabetic retinopathy, angiogenesis occurs in a less controlled manner (Forkman, J., Klagsbrun. M. Science 235: 442-447 (1987). Angiogenesis includes a series of processes such as the migration, proliferation and differentiation of endothelial cells, and is an important prerequisite for the growth and metastasis of cancers. In details because the growing tumor cells require the formation of blood vessels from host cells, angiogenesis promoters derived from tumors stimulate to induce the angiogenesis into the tumor mass. Afterwards, the blood vessels formed around the malignant tumors facilitate to metastasize the tumor cells to other sites. Therefore, the inhibition of angiogenesis leads to the prevention of the growth and metastasis of cancers. As one of the important research areas for the developing of anti-cancer drugs, extensive attention is paid to the finding of angiogenesis inducers and angiogenesis inhibitors and the revealing of their working mechanisms.
Because angiogenesis is a complex process with multiple, sequential and independent steps, it creates many potential targets for inhibition, including inhibition of angiogenesis inducers' production, inhibition of the binding of angiogenesis inducers to their receptors, inhibition of basal membrane degradation, inhibition of endothelial proliferation and migration, inhibition of capillary tube formation, and inhibition of basal membranes' syntheses and migration, etc. Thus far, proteins such as prostamine and tumor necrotic factors, polysaccharides, antibiotics, various steroid derivatives, polycataions, and polyanions have been found to be able to play roles as angiogenesis inhibitors. In particular, hydrocortisone exhibits anti-angiogenetic activity by cotreatment with heparin (Lee, A. et al., Science 221: 1185-1187 (1983); Crum, R. et al., Science 230: 1375-1378 (1985)). Recently Astra Zeneca's Iressa was launched for non small cell lung carcinoma, and several anti-angiogenic agents are currently in clinical trials. Neovastat, Tarceva, CAI and Thalomid are under phase III clinical trials with some positive results.
Ischemic heart diseases usually occur as a result of myocardial ischemia, when the oxygen supply is significantly decreased compared to the oxygen demand due to the imbalance between them. In most cases, a coronary artery disorder was found to be a main reason of the ischemic heart diseases. If the inner diameter of coronary artery becomes narrow, the blood supply, resulting in oxygen supply, becomes insufficient, which can cause angina pectoris, myocardial infarction, acute cardioplegia, arrhythmia, and so on (G. J. Grover, Can. J. Physiol. 75, 309 (1997); G. D. Lopaschuk et al., Science & Medicine 42 (1997)). Because ischemic heart diseases are also caused by other complex factors besides coronary artery disorders, drug therapy as well as operational method such as percutaneous transluminal coronary angioplasty (PTCA) is required for its treatment. For that purpose, several drugs are being used, including anti-thrombotic agents, arteriosclerosis, curatives, especially beta blockers, nitrate, calcium antagonists such as nifedipin, thromobolytics, aspirin, and angiotensin converting enzyme (ACE) inhibitors.
Differently from conventional potassium channel openers, the benzopyranyl anilinomethylimidazole compound (BMS-191095), has been reported to act selectively on ATP-sensitive potassium channels (KATP) located in the heart (K. S. Atwal et al., J. Mde. Chem. 36, 3971 (1993); K. S. Atwal et al., J. Me. Chem. 38, 1966 (1995)). The BMS 191095 compound was found to protect ischemic hearts without a significant lowering of blood pressure, which gives the prospects for novel drug development as a cardioprotectant.

Damage or death of neurons is known to be a main cause for various neurological disorders such as stroke, head trauma, Alzheimer's disease, Parkinson's disease, infant asphyxia, glaucoma and daiabetic neuropathy, etc. (G. J. Zoppo et al., Drugs 54, 9(1997); I. Sziraki et al., Neurosci. 85, 110(1998)). Neurons are damaged by various factors and typically by increases in iron concentration, reactive oxygen species, and peroxidants within neurons (M. P. Mattson et al., Methods Cell Biol. 46; 187 (1995); Y. Goodman et al., Brain Res. 706, 328 (1996)).
The intensive research on the development of compounds with the above-mentioned pharmacological efficacies by the inventors, found that the benzopyran derivatives substituted with secondary amines including imidazole represented by the formula 1. The compounds exhibit various pharmacological efficacies, including suppression of angiogenesis, in vivo anti-cancer activity, cardioprotection against ischemia-reperfusion injury, neuroprotective activity, prevention of lipid peroxidation and reactive oxygen species formation. Thus the compound of the present invention can be useful in the prevention and treatment of various diseases related to angiogenesis such as cancers, rheumatoid arthritis, and diabetic retinopathy; neuronal damage such as infant asphyxia, glaucoma, diabetic neuropathy and head trauma; oxygen free radical-related disease such as neurodegenerative diseases and atherosclerosis; and diseases related to cardiovascular system such as myocardial infarction, congestive heart failure, and angina pectoris.